High impact information on 8-Hydroxywarfarin

• R-warfarin is metabolized primarily by CYP1A2 to 6- and 8-hydroxywarfarin, by CYP3A4 to 10-hydroxywarfarin, and by carbonyl reductases to diastereoisomeric alcohols [1].
• Based on formation clearance values estimated for 6-, 7-, and 8-hydroxywarfarin, rifampin appears to increase the clearance of the parent drug by induction of the cytochrome P-450 isozyme(s) responsible for aromatic hydroxylation [2].
• Blood samples for determination of plasma warfarin and diltiazem concentrations, the prothrombin time and complete urine collections were obtained for determination of urinary excretion of dehydrowarfarin, 4'-hydroxywarfarin, 6-hydroxywarfarin, 7-hydroxywarfarin, 8-hydroxywarfarin and unchanged parent drug for 216 h after each dose [3].
• Based on the ratios of 6- to 8-hydroxywarfarin formed in two cultures, the ratios of CYP1A1/CYP1A2 expressed in these cultures were determined and they agreed with the ratios determined by immunoblot analysis [4].
• This assay has been validated from 2 to 1000 nM for 10-hydroxywarfarin and from 2 to 5000 nM for 6-, 7-, and 8-hydroxywarfarin and successfully applied to evaluate cytochrome P450-mediated drug-drug interactions in vitro using human hepatocytes and liver microsomal preparations [5].

Associations of 8-Hydroxywarfarin with other chemical compounds

• No deuterium kinetic isotope effect was observed for the formation of 6-hydroxy- or 7-hydroxywarfarin in the case of the (S)-6d1-warfarin metabolism by CYP2C9, or for the formation of 6-hydroxy-, 7-hydroxy-, and 8-hydroxywarfarin in the case of the (R)-6d1-warfarin metabolism by CYP1A2 [6].

Gene context of 8-Hydroxywarfarin

• Apparent Km values for the formation of 4', 6, 7, and 8-hydroxywarfarin indicated the presence of two easily distinguishable subsets of human liver cytochrome P-450; a high affinity subset (Km 3-15 microM) and a low affinity subset of isozymes (Km greater than 200 microM) [7].

References